The major finding is that there does not appear to be any difference in graft survival for young recipients transplanted at the pediatric center and those young adults transplanted at the adult center. Both groups appear to do worse than a slightly older cohort. This study does not provide any evidence that the transfer from pediatric to adult care is responsible for any increase in graft failure. The perception of early graft loss after transfer likely reflects advanced graft dysfunction in some patients. The more important implication of this report is our conception of the issue which might identify appropriate areas of study. Conceptually, it is not the transfer of care that is the critical issue but rather recipients, somewhere between the ages of 11-14 and 25, are a unique and vulnerable cohort. Effective strategies across this age group need to be identified and applied consistently.
The findings of this study appear to be at odds with a Government of Accountability Office (GAO-07-1117) report of US kidney transplant recipients. In an analysis of the USRDS database of kidney transplant recipients transplanted between 1997 and 2000, researchers also created 3 cohorts of patients (pediatric-1, 218, transition-2, 148 and adult-49, 940) and examined survival [5]. At 5 years post transplantation there were more graft losses in transitional patients (33%) than pediatric (16%) and adult (28%) patients. However, the Scientific Registry of Transplantation Recipients (SRTR) report showed that pediatric recipients between the age of 11-17 have the lower 1, 3, and 5 year graft survival compared to recipients age < 11 and age 18-34 [6]. The GAO study did not perform appropriate survival analyses, and neither the GAO nor the SRTR report tested for statistical significance in an adjusted model and did not distinguish between young adults (age 18-25) and older adults (age 25-35). We suspect that with further analysis of this registry, subjects transplanted within the 18-25 year age will be seen to have death censored graft survival rates that are similar to 11-17 year olds and both will be inferior to graft survival in 25 to 35 year olds. The Canadian study by Koshy et al found relatively constant graft loss rates of about 5-6 per 100 patient years of exposure in age intervals of 14-17.9, 18-19.9 and 20-23.9 [2]. Although some of the recipients transplanted at age 11-17 would have lost their grafts after transfer, the results would also be consistent with the concept that young adults somewhere between ages of 11 and 14 to 25 (the lower threshold is unclear) are a vulnerable cohort rather than the transfer of care being the critical issue.
The literature on transfer to adult care in kidney transplantation is limited. There is a concern that adolescents feel disenfranchised and alienated in the process [7]. Some have advocated a planned transfer that might include the adult nephrologist and nurse visiting the patient in the pediatric center prior to transfer, a joint transition clinic and programmed visits to the adult center prior to transfer [7]. However others have not been able to demonstrate the benefit of a targeted transition clinic [8]. The studies are small but all highlight the challenges of transfer. These and others are concerned about non-adherence [7–9]. It is possible that adolescents and young adults are at a vulnerable time regardless of the initial site of care and whether there is a transfer between centers. Greenstein and Siegal and others have characterized a subgroup of non-adherers as 'invulnerable'. These tend to be younger, less well educated, hide their non-adherence and do not believe missing medication will hurt them [9, 10]. Centers caring for adolescent and young adults may need to confront this specific belief.
The study did not find a greater rate of admitted non-adherence as a cause of graft failure despite our initial perception that this might explain observed differences. It is difficult to know the extent of the non-adherence in the entire group since often the admission is only detected at graft failure. No measures of non-adherence have high sensitivities or specificities [11]. We utilized admitted non-adherence with immunosuppressant medications as a specific variable in this analysis, but did not ask all patients in a standardized fashion [12]. We did not evaluate rates of covert non-adherence in this study (for example low or variable drug levels, unfilled prescriptions, etc). It is interesting to note that females had inferior outcomes in comparison to their counterparts. There is some suggestion that body image may play a role in non-adherence in pediatric transplant recipients however there was no clear indication of greater non-adherence in females in this study and gender has not consistently been associated with non-adherence in pediatric transplant recipients [13, 14]. Whether some of the difference in graft survival exists between the ADL group and the younger 2 cohorts from undetected non-adherence remains speculative.
Part of the perception that patients do worse after transfer is that some are transferred with failing allografts leading to dialysis within a short time period. Of the cohort transferred almost half have lost their transplant. Age was the reason for transfer, not graft function. Patients were transferred within a narrow age window but at a wide range of times from the date of transplantation and with a wide range of graft function. Many of the patients transferred have significant 'mileage' on their grafts and this is the more likely explanation for the perception of inferior outcomes. Overall the care of the patients at transfer was excellent with well controlled blood pressure and serum phosphate. It is interesting to note that the number of laboratory tests in the year after transfer was about half of the number in the year before transfer. Although there were significant differences in the types of initial immunosuppression between cohorts this did not explain the differences detected. Whether the differences in outcomes could be related to greater immune activity or greater non-immunologic (growth and hormonal changes) stress in younger recipients remain a distinct possibility and should not be discounted.
The study has limitations. To test the hypothesis adequately that transfer of care is the critical event there would need to be a control trial randomizing pediatric kidney recipients at age 18 to continued follow up at the pediatric center compared to transfer and follow up to an adult center. As analyzed in this study a significant difference between the pediatric and young adults could have been missed. A sample size of nearly 700 patients would be required to detect a hazard ratio of 0.80 with a power of 80%. This is a single center Canadian study in a predominately white population with universal health care. Other centers might experience different outcomes. A prospective comprehensive standardized non-adherence study would better detect this as a cause of differences in survival between cohorts than this retrospective analysis. We suspect that non-adherence remains a major explanation but cannot prove it.
Immunosuppression was significantly different between groups at baseline but was not a significant predictor of outcomes. This may have been the small sample size or the fact that many pediatric patients had medication changes, as demonstrated in the composition of drug therapies at transfer (Table 2). The more likely explanation is that the newer therapies have reduced acute rejection rates and improved 1 year graft survival but have not greatly improved survival after the first year [15]. In a recent study by Opelz, no significant survival differences could be detected between recipients treated initially with cyclosporine versus tacrolimus or mychophenolate versus azathioprine [16]. The finding that CMV D+R- recipients fared better was a surprise finding of the study and is largely unexplained. Most studies show that these recipients are at increased risk of both death and graft loss [17]. All patients would have received prophylaxis at both centers. The protocols have evolved over time with IVIG and acyclovir in the early years to the current strategy of oral valganciclovir.
